“I must rise above the culture of perfection

and remember that I can be even if I can

no longer do.”

Richard M. Cohen

AUTUMN 2007

www.ednf.org

L O O S E CONNECTIONS

TABLE OF CONTENTS

AUTUMN 2007

FEATURES

Book Review: HowDoctors Think ..................5Delayed Gratification .......8Musing AboutFundraising ....................10News Blitz Ideas ............14Brooke’s Story ................15

MEDICAL

FDA & Fibromyalgia ........7Self-association of Collagen .........................16

MEMBERSHIP & NEWS

Board of Directors ............2Submissions Guidelines ...3 President’s Award ............3Kids & Teens ....................6EDNF Research Results .11Local Groups ..................17Membership Form ..........18

This story was filed on Friday, August 3, 2007 6:26 PM CDT, and is copyright by Star Community Newspapers, Texas. It and similar stories about Nikki Darwin were carried first in Plano, and a month later the Dallas Morning News. In this issue, we’re focusing on individual efforts, carrying another piece run elsewhere, “Brooke’s Story” on Page 15 , and our “Golden Thread” stories on pages 8 and 10. At the end of Nikki’s story, you can find her mother (and EDNF Board Member) Michele Darwin’s accompanying notes, “News Blitz Ideas.” — Ed.

ThIs fall, John Paul II graduate Nikki Darwin, 18, will call Creighton University home for her first semester of college.

She plans to study nursing; a commendable career, but a far cry from her dream of playing basketball. But that dream came to a sudden halt during her junior year of high school.

After years of living a healthy and active lifestyle, the 6-foot-1 center began to experience back pains so unbearable she didn’t think she could continue playing. Her parents, Scott and Michele Darwin, became concerned because their daughter never complained. But suddenly she was contemplating ending her love affair with basketball.

At the age of 16, Darwin was diagnosed with Ehlers-Danlos syndrome, which is a defect in the connective tissue throughout the entire body. As a result of a lack of a protein called collagen, which acts as “glue” adding strength and elasticity to the connective tissue, Darwin does not receive the proper support in her muscles and ligaments. This tends to cause extreme cases of flexibility in the joints and can be very painful due to impact on the joints.

While sensitive skin problems are also a concern for EDS patients, Darwin’s main area of concern is in her spine, near her neck.

“Her brain stem droops down a little,” said Mrs. Darwin “Sometimes, if she moves her head in a certain direction, her spinal vertebrae put pressure on her brain stem which can cause problems in her neurosystem. Her spine is

DARWIN EVOLVES THROUGH THE PAINBY COrY J. MagEOrS, Staff WritEr, Star COMMUNitY NEWSPaPErS

(continued on page twelve, third column)

L O O S E CONNECTIONS

PUBLISHERS INDEX

Published Quarterly by Ehlers-Danlos

National Foundation

FOUNDERNancy Hanna rogowski1957 – 1995

President & CEOCindy Lauren

Board of Directorsrichard Blouserobin CoppiMichele Darwinrichard goldenhershJeanne KingsburyCindy LaurenCharlotte MecumDavid Specht

Professional Advisory NetworkPatrick agnew, DPMPeter Byers, MDEdith Cheng, MDJoseph Coselli, MD, faCCJoseph Ernest iii, MDClair francomano, MDtamison Jewett, MDMark Lavallee, MDHoward Levy, MD, PhDNazli McDonnell, MD, PhDDianna Milewicz, MD, PhDanna Mitchell, MD, PhDraman Mitra, MD, PhDLinda Neumann-Potash, rN, MNterry Olson, PtMary f. Otterson, MD, MSMelanie Pepin, MS, CSgElizabeth russell, MDUlrike Schwarze, MDKaren Sparrow, PhDBrad tinkle, MD, PhDMike Yergler, MD

EditorBarbara goldenhersh, PhD

Graphics/TypeMark C. Martino

PAGE TWO • aUtUMN 2007

DIRECTOR OF LOCAL GROUPS LAST REPORTBY CHarLOttE MECUM

I wIll be resigning my role as Director of Local Groups as of December 31, 2007. It has been an honor and

a privilege to work with the dedicated volunteers who have served as Local Group Leaders and Regional Coordinators (RC) during the past five years.

I have always been passionate about the importance of our Local Groups. They are essential in spreading awareness of EDS, educating medical professionals and communities about the disorder, and in providing support to individuals and families dealing with EDS. My feelings about the necessity of Local Groups will not change and I will continue to work in my own Local Group.

We have tried new structures and new programs for Local Groups during my time as Director. The increasing number of Local Groups and EDNF members and the progress of the Foundation have necessitated changes and adjustments to meet the changing needs. We have never lost sight of the fact that our Group Leaders are volunteers and have tried to make it as easy on them as possible, while abiding by the regulations EDNF must follow as a non-profit organization. I appreciate the acceptance and cooperation of Local Group Leaders as these changes have been made.

We will be establishing a new structure once again, with the beginning of 2008. All reports and paperwork for Local Groups will be handled by the National office. The Regional Coordinator program was discontinued as of July 15, 2007. Troy Winkels, previously an RC, will assist as new groups are organized and when groups apply for charter. Group Leaders will receive additional information about the structure for 2008 before the end of the year.

It is my hope that our Local Groups will continue to grow in number and accomplishments, making life better for those who live and deal with EDS.

Local Groups are a vital part of EDNF; the volunteers who take on the task of organizing, leading, serving as officers of Local Groups, as well as the individuals who participate as members of the Local Groups, are playing an invaluable part in making it possible for EDNF to carry out its mission.

I am very proud of our Organization and the resources and services it provides, and I am pleased to remain involved in it. I will have time to focus on other areas of EDNF’s work that are important to me. I urge each EDNF member, likewise, to find an area of interest in which you can volunteer your particular talents and skills. If you are interested in organizing a local group in your community, please contact Troy Winkels, wintr@hiwaay.net, or you can contact me at charlotte@ednf.org through the end of 2007.

My thanks to each of you involved in the work of Local Groups and best wishes for your continued success. ■ ■ ■

LOCAL GROUP LISTINGS CAN BE FOUND ON PAGE 18.

“I am still determined to be cheerful and happy, in whatever situation I may be; for I have also learned from experience that the greater part of our happiness or misery depends upon our dispositions, and not upon our circumstances.”

— Martha Washington(1731-1802)

GUIDELINES FOR SUBMISSIONSTO LOOSE CONNECTIONS

For text documents, use Helvetica or Times of at least 10 points (preferably 12 to 16) in size, so our editors can easily read your document and prepare it for publication. Attach the text document in either Word (.doc) or Rich Text Format (.rtf) to an e-mail sent to editor@ednf.org that also tells us how to reach you for more information.

For photographs, attach them to an e-mail to editor@ednf.org; send three to five images that are at least 2400 x 3000 pixels (300 dpi resolution & 8 x 10 inches) and without compression beyond that per-formed by the camera when it was taken. In the e-mail, please identify the event or cause for the photographs, including any relevant iden-tification (persons involved, date, photographer’s name if needed) and how to reach you for more information.

Following are the deadlines for the next year of four issues; special arrangements can be made with the editors before these dates, but not afterwards.

PUBLISHED ON

FEATURES DUE

COLUMNS DUE

WINTER ’07 DEC 7 OCT 19 NOV 5

SPRING ’08 MAR 14 JAN 25 FEB 15

SUMMER ’08 JUNE 23 MAY 16 MAY 30

FALL ’08 SEPT 5 JULY 25 AUG 8

Text articles, photographs, or any other submissions to Loose Connections are accepted only on condition that publication of that material is not under copyright or other restrictions on its publication. Ehlers-Danlos National Foundation reserves all and final editorial privileges, including the right to choose not to print a submitted story; submissions may be edited at the discretion of the editorial staff.

The opinions expressed in Loose Connections are those of the contributors, authors, or advertisers, and do not necessarily reflect the views of Ehlers-Danlos National Foundation, Inc., the editorial staff, Professional Advisory Network, or the Board of Directors.

EDNF does not endorse any products.

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2.

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L O O S E CONNECTIONSaUtUMN 2007 • PAGE THREE

$25 Donation to EDNFfor Active CarePages created at http://www.carepages.com/ednf

EhlErs-Danlos National Foundation has a proud history of volunteer service and we want

to reward your efforts. In recognition of these outstanding achievements, Ehlers- Danlos National Foundation is proud to announce the availability of the President’s Volunteer Service Award, a prestigious national honor offered in recognition of volunteer commitment. Established in 2003, this new Award is given by the President of the United States and honors individuals, families and groups who have demonstrated a sustained commitment

EDNF TO RECOGNIZE VOLUNTEERSTHROUGH PRESIDENT’S AWARDBY MiCHELE DarWiN

to volunteer service over the course of twelve months.

Our goal is to register all of our volunteers for this program. Our award year will run from July 1, 2007 through July 1, 2008. That means that any volunteer work done on behalf of EDNF since July 1, 2007 will be recorded. In order to participate you must register. Once you are registered you will receive a log to be completed monthly; you will receive reminders. For more information, or to register, please e-mail staff@ednf.org. ■ ■ ■

To be eligible to receive the President’s Volunteer Service Award,Applicants’ service hours must be confirmed by a registered Certifying Organization.

There are three levels of the Award varying byhours of service completed within a 12-month period:

Kids14 and younger

AdultsAges 26 and up

Bronze Award 50 - 74 hours Bronze Award 100 - 249 hours

Silver Award 75 - 99 hours Silver Award 250 - 499 hours

Gold Award 100 or more hours Gold Award 500 or more hours

Young AdultsAges 15 - 25

Families & Groups(two or more people, each contributing at least 25 hours to total)

Bronze Award 100 - 174 hours Bronze Award 200 - 499 hours

Silver Award 175 - 249 hours Silver Award 500 - 999 hours

Gold Award 250 or more hours Gold Award 1,000 or more hours

President’s Call to Service AwardIndividuals who have completed 4,000 or more volunteer service hours over the course of

their lifetime are eligible to receive the President’s Call to Service Award.

Between September 1 and December 31, 2007

And the Organization Generating the Most NEW Active CarePagesbetween September 1 and December 31, 2007Receives an Added $5,000

L O O S E CONNECTIONSPAGE FOUR • aUtUMN 2007

This year, EDNF will be printing a special insert in our December 2007 edition of Loose Connections. This special section will be dedicated to those who have done so much for EDNF this year, a listing of our donors and supporters. Now, we offer a chance to acknowledge our volunteers and share the dedication of our families with the entire membership.

Want to say thanks for a supportive voice, good advice or just a soft place to fall? Do you want to share someone’s memory? Let our members and friends know how much those people have helped. Below are samples of tributes that will be published in the next Loose Connections.

HALF COLUMN-INCH . . . . . . . . . . . $9 .00(1 .4 IN x 0 .5 IN, NO PICTURE)

ONE COLUMN-INCH . . . . . . . . . . $12 .50(1 .4 IN x 1 IN, NO PICTURE)

ONE COLUMN-INCH . . . . . . . . . . $17 .50(1 .4 IN x 1 IN, W/PICTURE)

EIGHTH-PAGE . . . . . . . . . . . . . $24 .50(4 IN x 2 .5 IN, W/PICTURE)

QUARTER-PAGE . . . . . . . . . . . . $47 .50(4 IN x 5 IN, W/PICTURE)

HALF-PAGE . . . . . . . . . . . . . . $85 .00(8 IN x 5 IN, W/PICTURE)

SEND PAYMENT TO EDNF (3200 WILSHIRE BLVD, STE 1601 S TOWER, LOS ANGELES CA 90010) AND AN E-MAIL TO EDITOR@EDNF .ORG BEFORE NOVEMBER 15, 2007 . INCLUDE IN E-MAIL YOUR DESIRED TExT; YOUR CHOICE OF TYPEFACE A, B OR C; AND IF APPLICABLE ATTACH PICTURE AT LEAST 1,200 PIxELS x 1,500 PIxELS IN SIZE .

Ty Beca

John Sebastian Brook J. & R. CarterQueen ColumbiaJohan CoriglianoFrank Lynn DeLanoMr. T. EseliotBill FinnTriale B. FireJohn GaltFrances GedroyceP.R. GiltTim & Ray GunnPhilip HaferClint Hilary

Mr. & Mrs. Tom Kruschev

Lorraine H. LiebersonMrs. Ronald McDougalIronic MensaA.Lias MonikerGuido O’MalleyJean O’Martin

Bama OnoConnie PowersMr. & Mrs. L.W. Priestley

I.Q. Public J.D. SalingerA. Ron SorekinMr. Gary ScullinStevie Songmeister

In memory ofDon Lee

Claire BlanCa special research volunteer, pan hinGe eDitor, eDnF/pan liaison

You have done and outstanding job. thank You so verY much!EDNF StaFF & BoarD oF DirEctorS

Campbell B. SuperiorE.D. SyndromesGertrude SteinmartMs Chiara StemmeAlice K. Tablas

Dr. Sol TardisJed Tate IVCapt. A. TenilleSam WhitingBryan Wingo

Have agreat year!

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�ou are sti� �� in�iration, �o�

� mi� �o�

L O O S E CONNECTIONSaUtUMN 2007 • PAGE FIVE

BOOK REVIEW

When you hear hoofbeats, think about horses, not zebras.

Common things are common.

In his book, How Doctors Think, Dr. Jerome Groopman challenges these maxims that interns are made to internalize during their training. In a poignantly-written chapter about a mother trying to understand the reasons for her adoptive daughter’s life-threatening illness, I was surprised to read these sentences, and Dr. Groopman’s request that doctors stop relying on them. He even states that the phrase “zebra retreat” describes when a doctor shies away from a rare diagnosis. He then postulates why doctors are reluctant to be “zebra hunters.”

Given that the phrase adopted by the Ehlers-Danlos National Foundation is asking doctors to be zebra hunters, it was refreshing to know there is a physician who sees problems with diagnostic processes. For Dr. Groopman, it is important that this message be brought to the public dialog.

The idea for this book came about when he was on rounds with his students. He noticed that they were not as engaged in diagnosing their patients or looking beyond the familiar as they could be. Students were taught to use algorithms for diagnosing, and those were relied on without any further attention. He questioned his own teaching skills, wondering how to get them to go beyond the first impression. This is when he first asked himself, “How do doctors think?” This meta-analysis took on new meaning when he was having difficulty with his wrist. Within three years’ time he saw six doctors and was given four different opinions, including four different surgery options. He wondered how the same issue could warrant so many different diagnoses and solutions. He wondered about lay-people who did not have the

benefit of having a medical background. How could they begin to navigate through such issues, especially when they had problems that needed time and investigation to reach the heart of the diagnosis?

With incredible openness, Dr. Groopman discusses what is taught in medical school, and what is not. He shows how doctors learn from the doctors before them, including surgical technique or types of medications prescribed. And he reminds us that if the doctors before have not learned or encountered obscure illnesses or disorders, then the interns and residents do not really learn much about these issues, either.

Additionally, Dr. Groopman opens the curtain and sheds light about a variety of people involved in the diagnostic process. He discusses radiologists and how they read x-rays, and how lab results are interpreted. He speaks about doctors who may be too quick to prescribe surgeries, and how pharmaceutical companies influence some doctors. What emerges is a book to which anyone who has ever had difficulty finding a diagnosis can relate, and because of the information presented, this can lead to any number of feelings.

Each person who reads this book is going to react differently; some may find it a validation, and some may find it frustrating — especially if they are still looking for a doctor or specialist to listen and understand what they are going through. Those of us, or our loved ones, who have finally been diagnosed with EDS may find ourselves thinking, “Have I got a story for him!” But Dr. Groopman has taken the first step. He has given us the background and the tools to talk to our doctors. The focus then needs to be on to taking that energy or anger and forming it into a positive device, using the suggestions in the book to help you

or your loved ones navigate through the medical establishment.

While Dr. Groopman does not think patients doing research is a bad thing, he reminds us that doctors spend years and years in medical school and many feel more than slightly put-off when a patient comes in with printouts and information about what they think they have. A contentious doctor may ask to keep the papers to look over and then do their own exam, perhaps scheduling another visit to go over both sets of information. Finding a doctor who will go that extra step may not be easy to do. However, in lieu of presenting the information straight out, he also recommends asking the doctor questions to help open up the communication of diagnosis.

He gives many examples on how to open this dialog, including practicing speaking about the symptoms and issues, keeping a calm head, and asking questions that go beyond yes or no answers. To facilitate appointments, write questions down, and highlight at least two or three you know you want answers to so you have direction. The key is to be calm, not intimidated or demanding. Dr. Groopman suggests to practice in front of a mirror (or with your best friend), and if you anticipate a brush-off, to have a follow-up question or statement ready.

Dr. Groopman stresses how patients and doctors must work together and that if an interaction is not a good fit initially, not to waste too much time trying to make it work. Ultimately, the doctor/patient relationship needs to be one of trust and communication. If these elements are not present with a doctor, perhaps when you decide not to see them anymore you can send the book as food for thought.

How Doctors Think, by Jerome Groopman, MD, was published by Houghton Mifflin Company, March, 2007. ■ ■ ■

HOW DOCTORS THINKBY JErOME grOOPMaN, MD • Reviewed by TRACY HORSTMANN

L O O S E CONNECTIONSPAGE SIX • aUtUMN 2007

According to a study published in the July 3, 2007, issue of Neurology, the medical journal of the American Academy of Neurology. For more information about the American Academy of Neurology, visit http://www.aan.com.

TeenAGerS from low income households with no family history of migraine are more

likely to suffer migraine than children from upper income families, according to a study published in the July 3, 2007, issue of Neurology®, the medical journal of the American Academy of Neurology.

For the study, researchers surveyed 18,714 adolescents and their parents. A total of 1,178 adolescents had migraine.

In households with an annual income lower than $22,500, the rate of migraine in teens without a parental history of migraine was 4.4 percent. In families earning $90,000 or more, the rate was 2.9 percent.

“Possible factors associated with low socioeconomic status, such as stress, poor diet or limited access to medical care may be responsible for this increase,” said study author Marcelo E. Bigal, MD, PhD, with Albert Einstein College of Medicine in Bronx, NY. “We plan to further investigate the role of nutrition, stress and treatment patterns since migraine may interfere with education, making it a public health concern.”

In families with a history of migraine, the rate of migraine among adolescents was nearly the same between both income groups. “It’s possible that in those with family history of migraine, the biological predisposition dominates and household income does not have a strong effect,” said Bigal.

The study found that overall 6.3 percent of teens experience migraine per year, with more girls than boys and more Caucasians than African Americans

experiencing migraine. The study also found most teenagers have one to four migraine attacks per month and most are severely impaired or require bedrest.

Bigal says the study is consistent with past studies which have found a strong relationship between migraine and low income in adults, but there are limitations. “Psychiatric factors, such as depression, anxiety, and substance abuse, were not measured in this study. It may be that these factors could explain the association between migraine and low income, which is why we need to better explore these factors,” said Bigal.

The study was supported by the National Headache Foundation.

The American Academy of Neurology, an association of more than 20,000 neuro log is t s and neurosc ience professionals, is dedicated to improving patient care through education and research. A neurologist is a doctor with specialized training in diagnosing, treating and managing disorders of the brain and nervous system such as stroke, Alzheimer’s disease, epilepsy, Parkinson’s disease, and multiple sclerosis. ■ ■ ■

KIDS & TEENSTeenagers from Low Income famILIes AT GREATER RISk OF MIGRAINE

MEDICAL ALERTBRACELETS should be an important part of the daily wardrobe for people with EDS, especially children and teens. There are obvious reasons for those with the vascular form of EDS but many with hypermobility form seem to think it isn’t necessary. In the case of an emergency it is vitally important that emergency rooms are aware of pre-existing medical conditions. We never plan for emergencies, but if they happen please be prepared and allow the medical staff the opportunity to know what they are dealing with. When noting Ehlers-Danlos on a medical alert, an emergency response team can call ahead so staff can be better prepared. Some medical alert companies offer computer thumbdrives which can make your medical history instantly available to a doctor with a computer. CRANIUM (FRONT)

L O O S E CONNECTIONSaUtUMN 2007 • PAGE SEVEN

how do you talk about a sensitive subject with your doctor? What if you forget

to ask an important question? What if you feel rushed during your visit? How can you get the most out of your visit with your health care provider? Being able to communicate openly, comfortably and assertively with your doctor can help you make good health decisions and stay well. But some older people shy away from this approach and hesitate to ask questions or take the doctor’s time.

The best patient-doctor relationships are more of a partnership, with both sides taking responsibility for good communication. To guide older patients in speaking with their doctors, the National Institutes of Health (NIH) offers Talking with Your Doctor, a newly released topic on NIHSeniorHealth.gov, a web site developed by NIH with the needs of older people in mind. The NIHSeniorHealth.gov web site is a joint effort of the National Institute on Aging (NIA) and the National Library of Medicine (NLM), which are components of the NIH.

“Most people know that communicating with their doctor is important to their health care, especially as they age and are more likely to have health conditions and treatments to discuss,” says Judith A. Salerno, M.D., NIA deputy director. “The key is to know how to have that conversation.”

Older adults can turn to this newest feature on the NIHSeniorHealth web site for information on managing conversations with their doctor. How to prepare for a doctor visit, what to ask, what information to provide, and how to understand what the doctor

NIHSENIORHEALTH.COM TIPSON TALKING WITH YOUR DOCTORfrOM NEWS rELEaSES

says are among the many helpful tips older adults can find on the site.

One of the fastest growing age groups using the Internet, older Americans increasingly turn to the World Wide Web for health information. In fact, 68 percent of wired seniors surf for health and medical information when they go on-line.

NIHSeniorHealth.gov is based on the latest research on cognition and aging. It features short, easy-to-read segments of information that can be accessed in a variety of formats, including various large-print type sizes, open-captioned videos and an audio version. The site also links to MedlinePlus (http://www.nlm.nih.gov/medlineplus/), the National Library of Medicine’s premier, more detailed site for consumer health information.

NIA leads the federal effort supporting and conducting research on aging and the health and well-being of older people. NLM, the world’s largest library of the health sciences, creates and sponsors web-based health information resources for the public and professionals.

The National Institutes of Health (NIH) — The Nation’s Medical Research Agency — includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov. ■■■

We include these reports from news re leases because many EDSers are a l so d iagnosed as having Fibromyalgia — Ed.

ThE U.S. Food and Drug Administration (FDA) recently announced the

approval of its first drug to treat Fibromyalgia. This announcement is one more step towards increasing recognition and validation by U.S. government health officials and others in the healthcare community of the seriousness of Fibromyalgia.

With the number of Americans suffering from this debilitating condition having risen in recent years to nearly 12 million, Fibromyalgia represents a population of nearly 4%, and can no longer be ignored by the medical community. While the need for continued research and studies still exists, the importance of the FDA announcement represents a change in acceptance as well as thinking.

As the FDA announcement permeates through the community of Fibromyalgia suffers, it is essential to understand the medical management required in treating this illness. Fibromyalgia treatment is not accomplished in a single short visit with a physician and a comprehensive approach is essential for successful results. ■ ■ ■

FDA’S EFFORTSHELP FIBROMYALGIAfrOM NEWS rELEaSES

“I am fond of only what comes from the heart.”

— Martha Washington

L O O S E CONNECTIONS

SHARING OUR GOLDEN THREAD STORIES

I mosT certainly would have been in intensive care had I not worn my seatbelt; I may have ended up

on the hood of the Jeep, or worse yet, melded together with the semi stacked high with two-by-fours. The sounds of colliding metal can be roughly compared to a crushing coke can, only a hundred times louder, and with enormous force. Surely, I was injured; luckily, I didn’t suffer even one cut. However, deep within my joints, I began to ache, and muscles in my neck and back tensed up as tightly as a guitar string. I had deeply and profoundly injured the soft tissue surrounding my shoulder, spine, knees and neck. I tore ligaments, tendons, and strained various muscles throughout my body.

After fours years of dealing with this new entity in my life, I awoke one January morning to a stabbing pain running the length of my spine as I sat up in bed. Two days later, I was diagnosed with long-term, progressive and degenerative damage to my lumbar spinal disc. I was twenty-three years old at the time. I would need fusion surgery, or at best, be the guinea pig for a new spinal device. I chose the device. As I sit typing, an artificial metal alloy disc sits between two lumbar vertebrae. Amazingly, it only feels slightly different from the real thing.

Days after this car accident, to deal with the stewing, mounting and erupting pain, I poured my heart out writing journal page after journal page. I tried, futilely, to explain my pain away, to act as though it were short-term, fleeting, and minimal. I wrote poetry, scribbled pictures, doodled endlessly, and even took up painting to occupy my mind; I had to deny this endless, throbbing pain; it was consuming my daily thoughts.

I have a high pain tolerance — I played years of basketball and religiously iced

DELAYED GRATIFICATIONBY OLiVia M KENNEtt

my ankles in buckets of near frozen water; but when constant, burning pain continues, you have to at least try to help someone else comprehend and share those feelings, or you’ll go crazy. Discussing subjective pain with family, friends, and colleagues became tiresome; I tried explaining aspects and technicalities of my complicated health issues to those who inquired. It’s tough trying to convince another person how pain has become your constant companion.

I desperately wanted to know why suddenly, at times, I couldn’t do simple things such as brush my hair without pain. I’ve experienced eight orthopedic surgeries. Throughout four years of college, I only played two years of my scholarship sport—golf. The rest of the time, I was on the surgery table, in therapy, icing my joints, and taking pain medication to control the aching. I was trying, without success, to do what I used to do the way I used to do it. No matter how often I thought I was healed, I began to ache with only a few days’ activity. I desperately wanted back the healthy, strong, injury-free body of my high school days that I painfully realized was forever changed. I was mourning the health that prompts grandparents to sigh in reflection, “Youth is wasted on the young.”

Ironically, or perhaps because of my humbling experiences, I continued my studies in the field of Exercise Science — a field not entirely suited for an individual in bodily pain, as the field depends largely upon daily exercise. Driven by an inner persistence to remain at least somewhat connected with the athletic field I had for so long been a part of, I became both an expert in the field of exercise techniques as well as a licensed teacher. I also completed graduate school to enhance and refine my knowledge.

I know about my body, I try to listen to it. I know how to tailor exercise for others so that they may become healthier or recover from injury. As a personal trainer and fitness advisor, I teach clients how to take care of their bodies. The satisfaction I would have received from excelling athletically or from the competition of sport is now equaled by a smile and a kind word from clients. In some small way, their accomplishments are my accomplishments.

I ’ve often experienced fatigue, impatience, frustration and exacer-bation of my own pain helping clients. Stretching a person’s legs or arms can be taxing on your own joints. Repeatedly lifting dumb bells can pull on scar tissue and inflame injuries. I knew I would have to cut my client load or stop altogether to maintain my own health. Deep down, I did not want to stop giving to others that which gave me joy, but I knew it was going to have to end sooner or later.

This spring, feeling at the end of my rope — physically, emotionally, and mentally, I learned something so cathartic that the anger I felt from years of painful injuries dissipated, like fog on a summer day. I was diagnosed on May 4, 2007 with Ehlers-Danlos syndrome, Hypermobile Type. It’s a long name for a simple syndrome. It gives cause,

PAGE EIGHT • aUtUMN 2007

L O O S E CONNECTIONSaUtUMN 2007 • PAGE NINE

as my doctor explained, as to why I’ve had so many recurring joint problems throughout the years. It also lends explanation as to why surgery has been ineffective at stabilizing my shoulder.

The moment the doctor said, “I think we have a diagnosis for you; you have EDS, and I think we’ve found a cause for your symptoms,” it was as if a weight rolled off my shoulders. I tried to subdue the upwelling of tears, but I started crying uncontrollably. The physician’s honestly expressed tenderness, so often unseen in the medical field, is perhaps partially explained because he also has EDS. He was the only person whom I had ever met who intimately understood how I was feeling. Even before he stated his diagnosis, his precise, accurate questions and observations of my physical and emotional condition made me hope he had some answer. It was as if he could read my mind. He could read the physical signs I unknowingly displayed. After his personal disclosure of living with EDS, I left his office numb, emotionally fatigued, but mentally refreshed. The uncertainty that was eroding my will to continue through pain had now been met with a reason and an answer.

Today, even as I write, I have a new outlook on things. No longer do I have to wonder why nothing is working to make me feel better — surgery, heavy pain medication, and physical therapy. I can now accept that because of EDS, coupled with exacerbation from the vehicle accident, my body will recover as best as the syndrome allows. The mental catharsis this diagnosis has given me is unbelievably reassuring. EDS is incurable; however, I am learning how to manage the chronic joint pain; I know it will never subside completely. I know I have EDS. Some things you just have to accept. This condition is one of those things. It is so much easier to face your foe, to know what he looks like.

I wonder how none of the previous physicians identified the parallels in my symptoms. For example, about two weeks before I was diagnosed, a surgeon I’ve seen for years asked me to “let him know” about the results from my consultation with the EDS specialist.

He said that if I did have EDS, it would explain the recurring surgeries. Knowing the true origin of the pain conditions, I sometimes wonder, “Why didn’t anyone tell me? Why couldn’t they at least have mentioned this as a far-fetched answer? How can well-educated orthopedists miss this?” The diagnosis could have prevented a lot of pain, anxiety, and frustration.

Ehlers-Danlos can be difficult to diagnose because those with Hypermobile Type are often healthy looking. The EDS specialist told me many of his patients are women; he even treats a few models. It is easier for some people, even doctors, to think patients could be exaggerating symptoms — even hypochondria. Many times, patients with EDS — Hypermobile Type are misdiagnosed as having Fibromyalgia or Chronic Fatigue syndrome; they do not necessarily show the more severe manifestations of the syndrome.

My relief at being diagnosed with a genetic syndrome may appear contra-dictory. However, one has to realize that for me, it is a piece of knowledge; it is an answer to an arduous journey and burning questions. Knowing the why enables me to grasp and justify past, present, and future pain. Before this diagnosis, I could only question, “Why isn’t anything helping?” Now, I am at peace with my lot in life. I don’t resent the pain any longer. I am useful, content, and enlightened.

I still have pain, but medication controls it. I am learning how to exercise and treat my body with extreme care so I don’t further weaken my joints. I’m becoming educated about the syndrome. There will be many more doctor visits and numerous tests. Granted, I will have to give up some things: personal training, contact sports, jump rope, running, and any sport that involves throwing or subjects my joints to less-than-favorable positions. For a person whose life is about fitness and sports, this is hard … but not impossible. ■ ■

L O O S E CONNECTIONSPAGE TEN • aUtUMN 2007

I h AV e a l w a y s h a t e d fundraising. Luckily, at PS101 in Brooklyn we did no fundraising

that required us to go door-to-door selling wrapping paper. There were a few exceptions however. We did collect pennies for UNICEF on Halloween but we were in costume so could not be identified (or so we believed). We collected dimes for the March of Dimes; money went to research a cure for polio. We also had punch boards; I cannot remember much about them, except that for 10¢ you could punch a spot on the board and receive a slip of paper informing you if you had won the jackpot. I cannot remember where the money went or if it was even a charitable fund raising. Since I lived in “Mafia Land” (part of The Godfather was filmed at a house on my corner), it is possible that it was a mob related activity. Even when my own children were in school, I would buy whatever they were selling, so they would not have to peddle their wares.

After being diagnosed with EDS at the ripe old age of 55, I joined EDNF and started a local group here in Atlanta. We did little fundraising, so I personally contributed whatever I could spare. Since I was actively employed at the time, I found it easier to make donations myself than to solicit others. Our group did decide to do fundraising by selling note cards with copies of pictures by a local artist — if anyone wants a box, please contact me as I have many left.

When I retired from teaching, my income was cut drastically. I could no longer fund our local group by myself. I did have more time to volunteer and

MUSING ABOUT FUNDRAISINGBY JUDY SOBEL

participated in national and local EDNF projects. But I still could not bring myself to activity solicit funds. I worked hard on preparing for the conference in Houston which was a great success, I think due mainly to Michele Hegler’s unceasing work in making it all happen. On the way home from the conference, my husband and I decided to take the long road home and vacation along the way. Everything was wonderful until we hit Jasper, Texas where I contracted a life-threatening case of e-coli.

I started to have severe stomach pain. Since I had already lost my appendix, I couldn’t imagine what was causing the excruciating pain. We stopped at a motel for the night on the Texas/Louisiana border.

The next morning, I couldn’t wake up; I was in a coma. My husband frantically called 911, and the ambulance took me to the nearest hospital, Our Lady of Lourdes in Lafayette, Louisiana. I didn’t come out of the coma until the next day, and I found myself in the ICU. It was determined that I had e-coli and aspiration pneumonia.

That was the sickest I had ever been. The severity of the attack was exacerbated by EDS. At my suggestion, Dr. Nazli McDonnell was called to confer on treatment. She was in the airport at the time bound for Turkey. She was able to speak with the staff and give them helpful hints on how to handle some of the problems I developed. I was moved to a regular room after about ten days in ICU.

We were getting ready to resume our journey back to Atlanta when I develpoped uncontrolled diarrhea and a grand mal seizure that lasted for eight hours. Back to ICU and many more tests: I now had moderate to severe neurological defects including loss of motor coordination, speech aphasia and apraxia and hearing loss. A wonderful neurologist who, in consultation with my neurologist in Atlanta, put me on a program of medication to control the seizures. Rehab was planned for me and begun in the hospital. I would not be released from the hospital, however, until an EEG showed that brain agitation had ceased. It took another ten days in ICU and three more EEGs until I was declared fit to travel. My son flew down to help my husband drive home so they could do the trip in one day.

After months of rehab, I have recovered some of the skills I lost. I still have a hearing loss, and — I who ran a computer training program for seniors — am slowly regaining my computer skills. I still have no balance and cannot step down off a curb without falling.

Why am I telling you all of this? A little self-analysis is called for at this point. Losing my father at an early age made me very independent. I hated asking anyone for help for anything. We were left almost penniless, and no family member stepped forward to help us. Not only did I not want to ask for help, I was also afraid of being turned down. Although I went out of my way to aid others, I still found it difficult to ask anyone for help for myself. I think the general consensus at the hospital was that the various

SHARING OUR GOLDEN THREAD STORIES

L O O S E CONNECTIONSaUtUMN 2007 • PAGE ELEVEN

and sundry EDS problems turned what should have been a painful but manageable illness into a life-threatening experience.

I realized that I could no longer send in my few dollars and expect EDNF to accomplish its very important goals which might have prevented or mitigated my problems. So I bit the bullet and launched into direct fundraising. I started by setting up a First Giving page and a goal of $600. I am proud to announce that I have already reached that goal and will now set another one.

You never know who is out there willing to help until you ask. This is from a letter I received from an old, but not very close, friend:

However, we will send the contribution of $500.00 in a day or so. Good luck. I know you pour your heart and soul into the organization.

If I can do it, so can you. ■ ■ ■

EDnF is proud to announce the results of new research directed toward gaining understanding of EDS. These two projects were sponsored by EDNF and administrated through National Organization for

Rare Disorders (NORD) using EDNF member donations of $70,000 and have come to fruition in an amazingly short two years. Margaret Casal, DVM, PhD and Anton Persikov, PhD each received a grant and both have completed their research projects. We include here the abstracts of their research.

establishing Molecular Basis of ehlers-Danlos Syndrome by Bioinformatics and Biophysics Approaches

Anton Persikov, PhD • Lewis-Sigler Institute for Integrative GenomicsPrinceton University

Dr. Persikov reports: Glycine mutations in type III collagen gene often lead to the vascular type of Ehlers-Danlos syndrome. My study showed that these substitutions result in destabilization of collagen triple helix, which varies depending on the amino acid residue replacing for glycine, as well as amino acid environment of the mutation site. The level of this destabilization may determine whether mutation will or will not lead to disease. In particular, when proline residue is found next to the mutated glycine, the triple helix destabilization is more dramatic, leading more frequently to pathological EDS phenotypes. The least destabi-lizing mutations, when glycine is replaced by alanine, cysteine or serine, and these residues are not followed by proline, lead to minimal destabilization of the collagen and normal phenotypes. I will continue studying how mutations observed in EDS affect collagen ability to bind other molecules in extracellular matrix. Understanding of molecular basis for EDS together with modern machine learning methods will allow prediction of phenotype from the knowledge of genotype. In another words, from DNA analysis it will be possible to predict whether alterations in collagen gene will or will not lead to disease.

Dr. Persikov has used the results of this study in two published research articles, available in whole on the EDNF Website:

Self-association of Collagen Triple Helix Peptides into Higher Order Structures

Y-Position Cysteine Substitution in Type I Collagen (a1(I) R888C/p.R1066C) Is Associated with Osteogenesis Imperfecta/Ehlers-Danlos Syndrome Phenotype

EDNF RESEARCH PRODUCES RAPID RESULTS Staff rEPOrtS

THE FOOT

L O O S E CONNECTIONSPAGE TWELVE • aUtUMN 2007

A Canine Model of Autosomal Dominant ehlers-DanlosMargaret Casal, DVM, PhD • Section of Medical GeneticsVeterinary Hospital of the University of Pennsylvania

The primary goal of this project was to provide a large animal (canine) model of the Ehlers-Danlos syndrome (EDS) to mechanism of disease. A female Labrador retriever with an autosomal dominant form of EDS was donated to the Section of Medical Genetics at the Veterinary Hospital of the University of Pennsylvania for characterization and expansion of this canine model. Initial studies included the identification of the defective gene and characterization of the disease to further strengthen the EDS dog as a model for the human disorder. To this end, skin biopsy samples were obtained from each dog under local anesthesia (as is routinely done in the clinical setting for canine patients), radiographs (X-rays) of all limbs were taken, and breeding studies are still being performed to confirm the mode of inheritance. Skin biopsy samples were examined by routine microscopy and electron microscopy. The biopsy samples were also examined for elasticity (tensile strength) and fragility. The hearts of all dogs were examined routinely by auscultation (stethoscope), EKG, and echocardiography (ultrasound of the moving heart).

In summary, our dogs show not only the same clinical and pathological features as humans with EDS but they also have the same problems with medical management such as placing IV catheters and local lidocaine application. Future experiments are directed at developing better methods for placing IV catheters, more effective local anesthetics and understanding reasons why the skin does not react to local anesthetics as it does in normal dogs. The ultimate goal is to use the EDS dog for treatment trials that would be curative rather than just palliative. We are in the process of establishing collaborations with the research dermatologists at The Thomas Jefferson University in Philadelphia, that have been using iRNAs (interfering RNAs) in mice with EDS. The iRNAs are designed to interfere with the production of the abnormal collagen molecule, so that only the normal fibers are generated. The funding received from EDNF through the NORD Foundation has enabled us to generate results that have led to submission of an NIH grant to further study clinical care and treatment of this and the other genetic skin diseases we work with. ■ ■ ■

unstable at the top and she has three herniated disks in her neck.”

Nikki is prone to imbalance in vision and range; sometimes waking up with one eye completely dilated while the other remains normal. At times even walking down a hallway can pose a challenge.

“I walk into walls and fall down sometimes,” Darwin said with a laugh. “I bruise really easily and tend to walk into a lot of things. My brother (John) has very sensitive skin; when he falls he gets some serious scars.”

EDS affects 1 in 5,000 people and has been found in Darwin’s 16-year-old brother John. Eleven-year-old brother Peter is involved in a clinical study at the National Institute of Health in Baltimore, Md., along with Nikki and John to better understand the inherited tissue disorder.

Playing for Meger

Nikki’s height was an obvious genetic advantage for her in most athletic sports, so before Darwin went to John Paul, Plano Senior head coach Lynn Meger saw visions of a future low-post dominator.

“(Darwin) was going to be one of my starters her junior and senior year,” Meger said. “As a coach you get a little excited about a player like that.”

Darwin was moved up to the varsity level early on and received a few minutes of playing time; enough to get some experience. But towards the end of Darwin’s sophomore season with the Lady Wildcats, back problems made it more difficult to practice and play.

“I told coach Meger and at first she asked me if I could fight through it,” Darwin said. “I would play a little and then I just couldn’t handle it. That’s when she realized something was really wrong and got worried.”

Meger couldn’t question Darwin’s toughness as she was a hard worker who gained the respect of her teammates.

After practices, Darwin would come home and lay flat out on the floor in pain that would last for days, sometimes weeks. Nikki saw a variety of doctors who were unable

(continued from front cover)

L O O S E CONNECTIONSaUtUMN 2007 • PAGE THIRTEEN

to diagnose her with anything specific, and being left in limbo became difficult.

“It was frustrating for me as her coach to know that she was in the amount of pain she was in,” Meger said. “On top of that, no doctors were able to help her and she was becoming frustrated as well.”

The educated mother

As any caring mother would do, Mrs. Darwin became as educated as possible, in hopes of finding a solution for her daughter’s ailments.

She took notes and researched nearly every clinical word the doctors threw her way. Initially, the doctors thought Darwin could have Marfan syndrome, which is a major cause of deaths among young athletes.

“If you ever see a kid just drop dead on the basketball court, often times it’s due to Marfan,” Mrs. Darwin said. “If Nikki was hit the wrong way or bumped or received the wrong impact of any sort that would have been it. So, she wasn’t going to be able to play anymore.”

However, after running tests, the doctors found no problems with Darwin’s heart and cleared her to play basketball again as long as she could deal with the pain. Some of the doctors suggested that it was possible Darwin was seeking attention and maybe that she even needed to see a psychiatrist.

“As her mother, seeing her go through this pain and knowing my daughter as well as I do, it hurt to hear them say that,” Mrs. Darwin said. “And for Nikki, as a teenager, it was hard for her to handle because she felt like people didn’t believe her.”

Thinking that she would be unable to continue playing basketball, Darwin transferred to John Paul during her junior year, where she thought she could concentrate more on her studies.

After doctor’s decided that she could continue to play, Darwin worked herself back in to playing mode under the instruction of head coach Lara Dinkins. But the pain still affected her on a daily basis.

One day sitting in class, Darwin sat silently and sent a text message to her mother telling her that she was in so much pain she was unable to get up and out of her desk.

With her teacher standing at the front of the class, Darwin didn’t want anybody to think she was complaining, but she had to reach somebody.

“I didn’t know what to do,” Mrs. Darwin said. “I asked her ‘How am I supposed to help you right now?’ But she didn’t want anybody to think she was complaining. That’s been the toughest part is getting her to realize that she’s not complaining if she needs help. She doesn’t want anybody to feel sorry for her; but if she needs help, she needs help.”

Still, Darwin’s passion for basketball was indescribable. While she played through the pain, her face never winced, but her body showed all of the signs.

“During one game, the team called a timeout and when Nikki came to the bench, she was just shaking,” Mrs. Darwin said.

Afterwards, Dinkins suggested to Mrs. Darwin that she send her information to her brother who is an emergency room doctor in Chicago. With tons of notes and a journal

kept as a file of her daughter’s symptoms, she forwarded the information along.

Within two hours they received a reply.

“Almot instantly, he called and said he thought she had Ehlers-Danlos,” Mrs. Darwin said. “He suggested we see Dr. Mark Lavallee, a sports medicine specialist in South Bend, Indiana. He himself had EDS and we took her to see him.”

Dr. Lavallee looked at her mouth, her legs and judged her flexibility. He did no brain scans or MRIs and diagnosed Nikki with EDS.

“I was sort of relieved because there was finally an answer,” Darwin said. “But he still wasn’t quite sure how to fix the pain in my back. I found out that a lot of the things I had done, I wasn’t supposed to do and I still find out things that I am not supposed to do.”

During her senior year, Darwin was unable to handle the pain any longer but still wanted to be part of the John Paul team. So she took a spot on the bench as a student assistant coach and helped the Lady Cardinals with an eye of inspiration.

“She was a very inspirational person for us as a player and as an assistant coach,” Dinkins said. “Nikki was right there beside me during home and away games, and we named her honorary co-captain of the team. She’s a very mature person for her age and I knew it was painful for her when she found out she couldn’t play. But she never got upset in front of the girls and never let it show.”

The National Honor Society and PAL’s took on a project with Darwin to sell John Paul crest charms at sporting events and throughout her senior year with all of the proceeds going to Nikki’s Charm Project Fund. She has already raised nearly $6,000 and continues to devote time to educating people about EDS.

As Darwin heads to college, she will still be faced with challenges along the way. Maintaining a healthy lifestyle and a proper exercise routine will be important for her body. Darwin does workouts that focus on her core, tightening her abs to support her back.

“Some days I feel like I worked out forever but never accomplished anything,” Darwin said. “Then other days I will wake up, not having done anything the day before and my muscles feel like I was hit by a dump truck.”

One of the more imposing tests will be making friends as Darwin will be faced with an entire group of new people to befriend at Creighton.

“I’ll let them know what they need to know as they need to know it,” Darwin said. “I don’t want to just spill my life story onto people right when I meet them, but as they need to find things out I will tell them.”

At the age of 18, Darwin’s maturity is abundant. Her hope is that more people become aware of EDS and that she can become a spokesperson, bringing a shred of optimism to those who are down.

“Yes I have it, but it is something that I can live with,” Darwin said. “I see some spokespeople who want others to feel sorry for them, but I want to let people know they can still enjoy life.”

For more information on Ehlers-Danlos syndrome, visit: www.ednf.org. More information on Nikki’s Charm Project Fund can be found at: www.firstgiving.com/nikkidarwin. ■ ■ ■

“I want to let people know they can still enjoy life.”

L O O S E CONNECTIONSPAGE FOURTEEN • aUtUMN 2007

You will notice we have included a number of media pieces in this issue. Many of us with EDS have tried unsuccessfully to obtain media coverage. Along with the published items, we share this overview of how it might be accomplished. — Ed.

EnGAGinG the media in our mission to raise awareness for Ehlers-

Danlos can be a daunting task. It can involve phone calls that go unreturned and e-mails with no replies, or the dreaded “auto reply” that leaves us to wonder if the e-mails are ever even read. There are, however, some tips that may lead to a successful media awareness campaign but it takes time to organize and patience on your part.

Begin by writing your story:

Try to keep your thoughts clear and concise. Your goal in writing your story is to get the attention of the readers by pulling on their heartstrings and show them you have some outcome you wish to reach: awareness, education, fundraising, etc. You want to get their attention! Remember that

newspapers and magazines have paid writers so it is unlikely they will publish your story as written, but if you can grab their attention, they will be interested in pursuing the story. Be very positive!

emphasize awareness and fundraising work related to the subject:

If the subject in your story has been raising money for EDNF or has been involved in anything relating to EDS and EDNF in your community then both briefly include that, as well as the link a FirstGiving or CarePage so the media can see the proof of the work being done.

Consult your physician:

Consult your physician and ask him/her to read your story to check for accuracy in your medical facts and ask permission to share their contact information with the media. Any story written about EDS that includes current and accurate medical references is far better than leaving it to the reader to fill in the blanks. Our doctors are very busy with other patients, but do try to see if they will at least critique your story before you distribute it.

Find the resources in your community:

Make a list of the print media in your town and surrounding neighborhoods. Start at the small community newspapers and end

NEWS BLITZ IDEASBY MiCHELE DarWiN

your list with the large paper that covers your area. Don’t forget the free magazines that may be published locally. If you aren’t sure what these might be, the Chamber of Commerce can be a great resource. As you look through the publications, you want to find the e-mail contact information for as many writers as you can. If you can’t find this information in the actual printed paper, go to their website to find them.

Create a Press Release:

Draft an e-mail that serves as a press release. It needs to be brief and effective! Compile an e-mail with the full list of recipients that you have found. Blind copy all of the recipients with the only e-mail address in the “to” line being your own. Include your press release, any relevant photos and your attached story.

The final step is to simply be patient and wait to see if you get any interest. ■ ■ ■

“The most difficult thing I have ever had to do is follow the gu idance I prayed for.”— Albert Schweitzer

L O O S E CONNECTIONSaUtUMN 2007 • PAGE FIFTEEN

BROOKE’S STORY:A DOUGLAS STUDENT FIGHTS A RARE DISORDERBY EMiLY MOOrHOUSE

Contact Brooke Friedman at cure4eds@aol.com. Emily Moorhouse is an intern studying journalism at University of Florida at Gainesville.

DeAlinG with a life-altering condition is distressing enough, but not knowing

what that condition is or what its effects are can be downright scary. For 14 years, this was the reality of Marjory Stoneman Douglas High School sophomore, Brooke Friedman, and her family. Brooke endures tremendous pain caused by the daily dislocations of her joints including her hands, wrists, ankles, knees, neck, fingers, and hips. Her parents began taking her to doctors at age two, and, throughout the years, she’s frequented the offices of eight different doctors. Each time, she was treated for the dislocations, but sent home with no firm diagnosis.

Not knowing what precautions were necessary for her “mystery” condition, Brooke and her family tried to go on with life normally. At five, Brooke began playing sports including T ball, softball, flag football, basketball, tennis, and bowling.However, as she got older Brooke’s dislocations increased to 12 to 15 times a day and her pain worsened, especially in her wrists and knees.When she went to camp in the mountains last summer, excessive walking caused her knees to buckle. “I was in pain the entire two weeks of camp and did not know why,” Brooke says. Thankfully, by August, she and her family had finally found a group of doctors who knew exactly that her pain was because of one of the six major types of Ehlers-Danlos syndrome (EDS), Hypermobility. A doctor of genetics and a pediatric orthopedics group at Joe Dimaggio hospital in Pembroke Pines provided the long-awaited confirmation.

Ehlers-Danlos syndrome is a genetic condition with, as yet, no cure. People with EDS have a defect within the collagen in their connective tissue, which normally works like “glue,” to support skin, muscles and ligaments and provide strength and elasticity. These individuals usually suffer from unstable joints, frequent dislocations, and joint pain, as well as fragile skin prone to tearing, bruising, slow healing, and severe scarring. EDS affects 1 in 5,000 people and life expectancy is usually normal, except for cases of the potentially deadly Vascular type, which thankfully, Brooke does not have.

In addit ion to frequent dai ly dislocations, Brooke is easily injured, resulting in “black and blue” marks that do not go away for months. Her muscles tire easily, and she has a very low pain tolerance. “When I go to the dentist, regular Novocaine doesn’t work,” she says. “I can exercise in the pool, that is about it… I can’t walk for long distances or for more than ten to fifteen minutes, I can’t walk up or down stairs [and] I can no longer play sports.” Yet, Brooke feels lucky, “some patients with EDS are confined to wheel chairs, no longer able to walk or use their hands to write.”

Since her diagnosis, Brooke is determined to bring awareness to others, to educate people on EDS, and raise money for research. She gives EDS presentations at schools and at doctor’s offices. This March, she arranged a “Change for Change” fundraiser

at Riverglades Elementary School from which she raised over $1200. She helped to administer the collection and spoke about EDS on the Riverglades television station. Brooke collects donations for the EDS National Foundation on her website,www.firstgiving.com/edsdonation. Her goal is $10,000 and, currently, she has raised nearly $2,100, with more expected.

Brooke also started a recycling drive for cell phones and ink/laser cartridges at Parkland’s public schools, as well as some local businesses. With these drives, Brooke has put in over 150 volunteer hours and has already collected over $600 for EDS. “Stoneman Douglas has been very supportive... students are so wonderful and receptive to helping with donating their old cell phones,” Brooke says. “I plan to continue this collection drive for the next school year and, if it goes well, continue on through high school.”

Brooke’s family has been extremely supportive. “My mom is very active with the national foundation and the EDS local chapter,” explains Brooke. Mrs. Friedman speaks to local groups about EDS and has even hosted some meetings in their home.

Although EDS has put a significant strain on Brooke’s daily life and she is saddened that she cannot partake in sports or much physical activity, she contends, “I don’t feel any different, I feel like a normal 10th grader, a very normal teenager. I love life and I love living in Parkland. I have a wonderful group of close friends and we have a great time together. Nothing stops us from having fun…I have decided to make a difference and turn this into a positive situation.” ■ ■ ■

Brooke is determined to bring awareness to others, educate people on EDS, and raise money for research.

L O O S E CONNECTIONSPAGE SIXTEEN • aUtUMN 2007

This is extracted with permission from the full paper. We urge you to read the complete text, available at www.ednf.org (Medical Professionals section under Medical Reports and Findings) or at http://www.jbc.org. To respond, write editor@ednf.org; always consult your doctors before making changes in your treatment.

* This work was supported in part by National Institutes of Health (NIH) Grant GM60048 (to B.B.). The on-line version of this article (available at http://www.jbc.org) contains Figs. 1-12.

1These authors contributed equally to this work.; 2Supported by NIH Predoctoral Research Fellowship Award F31 GM072149; 3Supported by a grant from the National Organization for Rare Disorders; 4Supported by a Deutsche Forschungsgemeinschaft postdoctoral fellowship; 5To whom correspondence should be addressed: Dept. of Biochemistry, UMDNJ-Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854. Tel.: 732-235-4397; Fax: 732-235-4783; E-mail: brodsky@umdnj.edu; 6The abbreviations used are: DSC, differ-ential scanning calorimetry; DLS, dynamic light scattering; PBS, phosphate-buffered saline. — Ed.

IntroductionThere is increasing interest in the ability of proteins and peptides to self-associate into aggregates, both in normal and pathological processes. Normal self-association processes include fibril formation of collagen and polymerization of actin, whereas pathological aggregation of amyloid peptides, -synuclein, and prions is implicated in neurodegen-erative diseases. Interest has focused on the nature of protein aggregation and the molecular and environmental determinants of the self-association process. The study of the ability of collagen-like peptides to aggregate offers an opportunity to characterize a unique system, which may relate to the

physiological self-association of collagen molecules.

Collagen, the major structural protein in the extracellular matrix, has a charac-teristic triple helical conformation, consisting of three polyproline II-like chains that are supercoiled around a common axis. The close packing of the three chains near the central axis generates a requirement for Gly as every third residue, (Gly-X-Y)n, whereas the high content of imino acids Pro and hydroxyproline (Hyp) stabilizes the individual polyproline II-like helices. Although imino acids are highly favorable for the triple helix, the post-translational modification of Pro to Hyp in the Y position confers an additional stabilizing contribution. This further stabilization of Hyp is likely to result from steroelectronic promotion of the more favorable exo ring pucker for the Y position and Hyp involvement in solvent-mediated hydrogen bonding. The favorable enthalpy of collagen indicates that hydrogen bonding is a major contributor to stability. One direct interchain peptide hydrogen bond is formed for each Gly-X-Y unit, together with an extensive water-mediated hydrogen bonding network. The ordered water network seen in crystal structures links the available backbone carbonyls of the triple helix and Hyp groups.

The family of collagens consists of 28 distinct genetic types with a range of tissue distributions and diverse functions. For most collagens, the molecules self-associate to form a higher order structure, such as fibrils and networks, and the supermolecular structure is responsible for mechanical and binding properties critical to function. The most abundant collagens are types I, II, and III, which are found in characteristic fibrils with an axial D = 670 Å period in tendon, skin, bone, cartilage, and other tissues. The process of association of type I collagen molecules into fibrils has

been characterized from thermodynamic and kinetic approaches. In addition, the assembly of type IV collagen into networks in basement membranes and the organization of type VII collagen association in anchoring fibrils of skin are beginning to be defined.

Studies of model peptides have contributed much to the understanding of the structure, stability, conformation, and dynamics of the collagen triple helix. The sequence Gly-Pro-Hyp is the most stabilizing and common triplet in collagen and the peptide (Pro-Hyp-Gly)10 forms a highly stable triple helix. The molecular structure of (Pro-Hyp-Gly)10, determined to high resolution by x-ray crystallography, confirms the basic triple helical structure and shows an extensive hydration network. Recently, there have been several reports of collagen-like peptides that self-associate to higher molecular weight structures, including studies on poly(Pro-Hyp-Gly)10, staggered arrangements of (Pro-Hyp-Gly)10 chains, and liquid crystalline arrays of triple helical peptides. Cross-linked, high molecular weight forms of (Pro-Hyp-Gly)10, but not the (Pro-Hyp-Gly)10 molecule itself, have previously been shown to function as strong inducers of platelet aggregation. Thus, peptide studies may increase our understanding of the formation and biological activity of the polymeric collagen structure as well as giving information at the molecular level.

Here, self-assembly of the collagen model peptide (Pro-Hyp-Gly)10 is characterized by a range of biophysical techniques, including turbidity, CD spectroscopy, differential scanning calorimetry (DSC),6 dynamic light scattering (DLS), and electron microscopy. The peptide is shown to self-associate with increasing temperature, following a nucleation-growth mechanism, from a simple trimer to a higher molecular weight form. This process is promoted by high concen-

fUNDED iN Part BY tHE NiHseLf-assocIaTIon of coLLagen TrIPLe HeLIc PePTIDesINTO HIGHER ORDER STRUCTURES*BY kARUNAkAR kAR1, PRIYAL AMIN1, MICHAEL A. BRYAN2, ANTON V. PERSIkOV3, ANGELA MOHS4, YUH-HWA WANG, AND BARBARA BRODSkY5

L O O S E CONNECTIONSaUtUMN 2007 • PAGE SEVENTEEN

tration, neutral pH, increasing peptide length, and increasing temperature and is a reversible process. The self-association properties of this triple helical peptide are discussed in the context of collagen fibril formation.

MATERIALS AND METHODS

The peptide (Pro-Hyp-Gly)10 was obtained from Peptides International (Louisville, KY). The peptides (Pro-Hyp-Gly)7, (Pro-Hyp-Gly)8, and (Pro-Hyp-Gly)12 were synthesized by the Tufts University Core Facility (Boston, MA) and were purified on a reverse-phase high pressure liquid chromatography system (Shimadzu) with a C-18 column. Purity of all peptides was ensured by mass spectrometry using matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF). Peptide concentrations of starting solutions were measured by monitoring the absorbance at 214 nm using 214 = 2200 cm-1·M-1 per peptide bond. D-Glucose and D-fructose were obtained from Merck. Buffers used included 20 mM PBS (10 mM NaH2PO4, 10 mM Na2HPO4, 150 mM NaCl) for pH 7; acetate buffer (20 mM sodium acetate, 150 mM NaCl) for pH 3.0-4.5; and phosphate buffers (20 mM Na2HPO4, 150 mM NaCl) for pH 9-11.

DISCUSSION

The triple helical peptide (Pro-Hyp-Gly)10 is reported here to self-associate under defined conditions of concentration, temperature, and pH. The turbidity curve monitoring self-association is similar to that seen for collagen fibril formation and the polymerization of other proteins, in having a lag or nucleation phase followed by a rapid growth phase and a plateau. A nucleation-growth mechanism was confirmed by seeding experiments, which eliminated the lag phase. Consistent with this mechanism is the concen-tration dependence of the aggregation of (Pro-Hyp-Gly)10, which shows a critical concentration of about 1 mM.

The lag phase decreases, whereas the rate of fibril growth is enhanced with increasing temperature, with a maximum rate occurring somewhat below the Tm of (Pro-Hyp-Gly)10. The effect of temperature on the rate of association

gave a linear Arrhenius plot with a negative slope. The promotion of self-association with increasing temperature suggests the energetically unfavorable formation of a nucleus during the lag phase is entropically driven. Increasing temperature could loosen the triple helix and its associated water, which may promote self-association. A schematic diagram of the self-association process for (Pro-Hyp-Gly)10 is shown in Fig. 7, suggesting an intermediate loosened state of the triple helix, which has a propensity for association. This is reminiscent of the temperature dependence of assembly of collagen into fibrils, which has been analyzed in terms of forces. Leikin et al. showed this “temperature favored” process of collagen fibril formation is largely because of hydrophilic interactions, which could relate to release of structured water or increasing mobility of side chains. In the case of (Pro-Hyp-Gly)10, it is possible that a small increase in mobility of the rigid imino acids could play a role, but it is more likely that loosening of the ordered hydration shell due to increasing temperature is an important factor. Leikin’s laboratory has shown that sugars inhibit fibril formation of collagen by disrupting water mediated hydrogen bonds between triple helices, and the inhibitory effect of sugars on the self-association process of (Pro-Hyp-Gly)10 seen in our present work indicates a similar importance of hydration related hydrogen bonding for the peptide association.

A strong length dependence is observed for peptide association. An increase in peptide length could either lead to a larger number of cooperative interactions or promote a molecular crowding effect because of the larger hydrodynamic radius of a longer rod-like molecule. Consistent with molecular crowding, it has been reported that aggregation of several collagen-like peptides can be induced by very high concentrations (>10 mM). Higher molecular weight peptides and cross-linked trimers of staggered chains with the sequence Gly-Pro-Hyp form aggregates with a morphology similar to that reported here.

Self-association also depends on pH, with an optimum near neutral pH and no aggregation at low and high pH

values. The pH dependence of the self-association could be related to water activity, or association could be promoted by lower thermal stability and a resultant loosening of the triple helix, because the melting temperature of (Pro-Hyp-Gly)10 shows a small decrease near neutral pH.

The observation that a homologous triple helical peptide (Pro-Pro-Gly)10 does not come out of solution under the conditions used in this study suggests that all triple helical peptides do not have the same propensity for self-association. The differences observed between (Pro-Pro-Gly)10 and (Pro-Hyp-Gly)10 suggest a role for Hyp in promoting self-assembly, which is supported by the observation that recombinant collagen without Hyp does not undergo fibril formation under physiological conditions. The role of Hyp in triple helix association could relate to its involvement in the hydration network or to direct intermolecular hydrogen-bonding interactions between triple helices as observed in the crystals of collagen-like peptides or as proposed by Gustavson in the 1950s. Preliminary observations in our laboratory on various triple helical peptides with diverse sequences sandwiched between terminal Pro-Hyp-Gly repeats indicate that self-association is negatively influenced by the presence of charged residues, a Gly substitution, or an imino acid-deficient zone, in contrast to the positive influence of Hyp residues.

The aggregation of (Pro-Hyp-Gly)10 is reversible. The triple helical peptide comes out of solution as the temperature is increased, forming some supramo-lecular structure of triple helices. However, at temperatures higher than 80 °C, the aggregate fully dissolves into denatured monomeric chains. When cooling the unfolded monomers, the triple helix can re-form in a reversible manner, and while in the aggregation temperature range (37-60 °C) there is again aggregation of these refolded triple helices. Interestingly, both the monomer-trimer transition and the trimer-aggregate transition appear close to equilibrium.

The results reported here indicate that the triple helical (Pro-Hyp-Gly)10

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molecules are self-associating to form a higher order structure, which is more stable than the individual triple helices and which is fully reversible. For the peptide, interacting triple helical molecules give rise to branched, fibrillar structures with no long-range order, which contrasts with the highly ordered axially periodic fibrils formed by type I collagen molecules. The short length of the model peptides and the uniformity of sequence are likely to contribute to its less ordered, branched structure and its high critical concentration value. Similar to the peptide association, collagen self-association into fibrils is reversible unless aldehyde-mediated covalent cross-links are formed. We suggest that the lateral self-assembly of triple helices may exhibit similar properties because of their common Hyp-mediated hydration networks. These hydrogen-bonding hydration networks involving Hyp are inherent in the molecular structure of the triple helix and serve to provide regular hydrogen bonding with the two available backbone carbonyl groups within each Gly-X-Y unit. Such hydration forces have been implicated as critical to the lateral fibril organization.

Physiological interactions often depend on collagen being present in fibrillar or other higher order structures. For example, platelets are activated by collagen via glycoprotein VI; this activation can be mimicked by a cross-linked higher molecular form of (Gly-Pro-Hyp)10 but not by the triple helical (Gly-Pro-Hyp)10 molecule. Similarly, binding to certain integrins may involve collagens in a fibrillar form. The ability to study the association of triple helical peptides may provide a tool for investigating interactions that require higher order structure as well as clarifying the principles of triple helix self-association. Elucidation of the principles of triple helix self-association may also be important in the design of biomaterials and tissue engineering scaffolds. ■ ■ ■

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Where is that hand?By Ellen Smith (7/18/2007)

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